Genetic Biocontainment Switch to Improve the Safety of Drug Detoxifying Bacteria in Preventing Chemotherapy-induced Diarrhea

PROJECT SUMMARY Bioengineered microbes are a promising strategy to develop live biotherapeutic products that can introduce novel metabolic activities into the gut microbiome and digestive system for the prevention and treatment of several gut-related diseases/disorders. Sanarentero is developing novel drug detoxifying bacteria (DDB), which is a bioengineered live biotherapeutic product that

can detoxify gut-toxic drugs causing chemotherapy-induced diarrhea in cancer patients. Successfully addressing a major biosafety concern (i.e., the transmission of genetically modified microbes into humans and environments) will make our product much more competitive since it will improve clinical adaptability and aid the regulatory approval of our product. Towards improving

the safety profile of DDB, we are introducing a genetic biocontainment switch in our product that can be triggered to contain the engineered metabolic function as and when needed. Our unique genetic biocontainment switch (GBS) not only is designed to prevent the engineered metabolic pathway genes to escape from a designated environment but also performs its function without

killing the microbes to minimize the cellular burden and genetic instability. The overall goal of the project is to establish the activity and safety of drug detoxifying bacteria equipped with the proposed genetic biocontainment switch (DDB_GBS) in an animal model. To achieve this goal, the three specific aims of this phase 1 STTR proposal are 1) to bioengineer genetic

biocontainment switch into DDB; 2) to develop a delayed-release formulation of DDB_GBS for improved intestinal engraftment; and 3) to evaluate the safety, glycosylation function, and biocontainment efficiency of DDB_GBS. The success of this project is the proof-of- concept evidence of our approach for developing novel drug detoxifying bacteria with a safety

feature that can detoxify cancer chemotherapeutic drugs in the gut environment towards preventing chemotherapeutic-induced diarrhea in cancer patients. Once the biocontainment efficiency of DDB_GBS is established, we will work on establishing the preclinical efficacy and manufacturing scale-up in the GMP facility for a phase II SBIR proposal.